Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 odds ratio (OR) 0.87; P 5 1.1 3 10 28 and rs4711751 on 6p12 near VEGFA (OR 1.15; P 5 8.7 3 10 29 ). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genomewide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD. c Replication P-values and ORs were derived from meta-analysis results of all replication samples independent of the TMMG sample. d Samples participated in the combined analysis for each SNP were indicated by letters (A/a to K/k). A capital letter indicates the effective allele of the SNP-increased risk of AMD in the specific sample. A lower case letter indicates the effective allele of the SNP-reduced risk of AMD in the specific sample. 'a' represents Tufts/MMAP/MIGen/GAIN (TMMG) samples; 'b', deCODE genetics sample replication (Iceland); 'c', the Columbia University sample replication (COL); 'd', the Johns Hopkins University sample replication (JHU); 'e', Genentech sample replication (Genentech); 'f', Washington University sample replication (WASH-U); 'g', the Centre for Eye Research Australia sample replication (AUS); 'h', the Rotterdam study sample replication (RS); 'i', the independent replication sample of Tufts/MGH (Tufts/MGH replication); 'j', the Hopital Intercommunal de Creteil sample replication (FR-CRET); 'k', the Queen's University of Belfast sample replication (Irish). e The result of this SNP was from imputation data based on HapMap2 Project; all other SNPs were imputed based on 1000 Genomes Project.